Preparation of alpha-acetamidobeta-hydroxypropiophenones



Patented Oct. 13, 1953 PREPARATION OFALPHA-AoErAMmonnm-nrnaoxrraorrornnnonss Delaware Oliver De Garmo, St.Louis, and David B. Guthrie,

Glendale, Mo., assignors Company, St. Louis,

to Monsanto Chemical Mo., a corporation of N Drawing. Application March14,1951, Serial No. 215,662

13 Claims. (01. 260-562) 1 This invention relates toalpha-acetamidobeta-hydroxypropiophenones; more specifically, thisinvention relates to an improved process for the production ofalpha-acetamido-beta-hydroxypropiophenones having the formula wherein Rrepresents a phenyl radical. 7 I

a-acetamido#3-hydroxypropiophenones are valuable intermediates in thepreparation of pharmaceuticals. Heretofore these materials have beenprepared by the hydroxymethylation of a-acetamidoacetophenones. Thisprocess was carried out by the reaction of a-acetamidoacetophenones withformaldehyde in the presence of a small amount of sodium bicarbonate,and this reaction may be represented by the following equation:

wherein R represents a phenyl radical. This method of preparation asheretofore used resulted in an erratic and unfavorably low yield of thedesired product.

It is an object of this invention to provide an improved process for thepreparation of a-acetamido-,B-hydroxypropiophenones. Further objectswill become apparent from a description of the invention which follows.

It has now been discovered that if the reaction of ana-acetamidoacetophenone and formaldehyde is carried out under controlledpH conditions, a highly improved yield ofa-acetamido-fihydroxypropiophencne results. According to the novelprocess of thi invention, therefore, highly improved yields ofa-acetamido -hydroxypropiophenones are obtained by reacting ana-acetamidoacetophenone having the formula:

R t st. tH O=CHs wherein R represents a phenyl radical, and form'-aldehyde while maintaining a pH below about 9.0 and preferably in therange of from about 8.0 to about 9.0, The following examples areillustra- 2 tive of the novel improved process of this inven* tion:

Example I 18.2 g. of p-nitro-a-acetamidoacetophenone is slurried in 63.5ml. of 95% ethanol and 22.5 ml. or water. While maintaining atemperature of about 30-35 (3., 14.4 ml. of a 37% formaldehyde solutionand 0.85 g. of sodium bicarbonate are added. The resultant mixture isstirred for approximately two hours while maintaining a temperature ofapproximately 30-35? C. during which time small amounts of glacialacetic acid are periodically added in order to maintain the pH of thereaction mixture in the range of from about 8.0 to about 9.0. A total ofabout 0.4 g. of acetic acid is required for this purpose.

The batch is then cooled to about 5 C. and the p-nitroa-acetamido-,3-hydroxypropiophenone filtered therefrom. The filter cakeis washed with water, a dilute hydrochloric acid solution and flnallywith another portion of water. The washedp-nitro-a-acetamido-fi-hydroxypropiophenone is then dried. The amount ofp-nitro-a-acetamidofl-hydroxypropiophenone recovered representsapproximately an 86% yield based upon p-nitroa-acetamidoacetophenoneinitially charged.

Example II I added during the reaction and no attempt is made to controlthe pH during the reaction. Approximately a yield ofp-nitro-a-acetamido-fihydroxypropiophenone is obtained.

Example III Example IV The procedure set forth in Example I is repeatedutilizing 16.1 g. of p-chloro-a-acetamidoaceto'- phenone in place of the18.2 g. of p-nitro-a-acetamidoacetophenone. An excellent yield ofpchloro a acetamido-13-hydroxypropiophenone is obtained.

Example V The procedure set forth in Example I repeated utilizing 16.4g. of D-mQ hOXy-u agefbam, idoacetophenone in place of the 18.2 g. .ofp-nitrovw-acetam'idoacetophenone. An excellent yield of p methoxy cacetamido B hydroxypropiophenone is obtained.

Example VI The procedure set forth in Example I is repeated utilizingpotassium carbonate in place of the sodium bicarbonate and sulfuric acidin place of the acetic acid to maintain the pH of the reaction mixturein the range of from 8.0 to 9.0. The yield ofp-nitro-a-acetamido-;3-hydroxypropiophenone thus obtained is comparableto that obtained in Example I.

While the preceding examples have set forth specific embodiments of thenovel improved process of this invention, it will be obvious to thoseskilled in the art that a substantial variation in these examples ispossible without departing from the scope of this invention. Anyv.acetamidoacetophenone having the formula Rl CHi NH 0 -15-011: whereinR. represents a phenyl radical may be utilized in the novel process ofthis invention. The phenyl radical can be unsubstituted or substitutedwith one or more substituents. Typical, but not limitative, of suchsubstituents are the halogens such as chlorine, bromine, iodine andfluorine; nitro groups; alkyl radicals such as methyl, ethyl, propyl,isopropyl, butyl, etc.; alkoxy groups, such as methoxy, ethoxy, propoxy,etc.

The quantity of reactants utilized in the novel process of thisinvention may be varied over a substantial range. It is preferred thatat least a one molecular proportion of formaldehyde be utilized for eachone molecular proportion of aacetamidoacetophenone. While it ispreferred that monomeric formaldehyde be utilized in the novel processof this invention, and preferably in the form of an aqueous solution offormaldehyde, the formaldehyde may be supplied or used in its polymericform, i. e., as paraformaldehyde. Excessive quantities of formaldehydehave no deleterious effect upon the reaction, and as high as four oreven ten molecular proportions of formaldehyde may be utilized for eachone molecular proportion of e-acetamidoacetophenone.

The reaction may be carried out in any type of an inert liquid medium.Typical of such mediums are water. the various alcohols, etc.Particularly useful reaction mediums are mixtures of water andwater-miscible organic solvents such as methyl and ethyl alcohol.

The temperature at which the novel improved process of this invention iscarried out may also be varied over a substantial range. It ispreferably carried out at a temperature in the range of from about 20 C.to about 50 C. although it may be carried out at any temperature betweenthe freezing point and boiling point of the reaction mixture eitherunder atmospheric pressure, sub-atmospheric pressure orsuper-atmospheric pressure.

According to the novel process of this invention, the pH of the reactionmixture is maintained below about 9.0 throughout the major portion ofthis reaction and preferably in the range of from about 8.0 to about9.0. This pH control is obtained by the addition of suitable basic oracidic agents as the case may be. Typical of the basic agents which maybe utilized are the alkali metal carbonates and bicarbonates, such asthe carbonates and bicarbonates of sodium and potassium, alkalinephosphate salts, the various alkali metal and alkaline earth metalhydroxides, sodium acetate, etc. The various acidic agents which may beutilized to effect proper pH control are illustrated by acetic acid,phosphoric acid, sulfuric acid, hydrochloric acid, etc.

After the reaction is complete, the a-acetamidofi-hydroxypropiophenonemay be recovered from the reaction mixture by any method well known tothose skilled in the art. Preferably, theaacetamido-;s-hydroxypropiophenone is separated from the reactionmixture by cooling and recovered by filtration.

What is claimed is:

1. In a process for the preparation of anacetamido-c-hydroxypropiophenone, the step comprising reacting ana-acetamidoacetophenone having the formula 0 ll RCCH| NH O=-CH:

wherein R represents a phenyl radical selected from the class consistingof the unsubstituted phenyl radical and substituted phenyl radicalscontaining as their substituent groups halogens, nitro groups, alkylgroups, and alkoxy groups; and formaldehyde while maintaining a pH inthe range of from about 8.0 to about 9.0.

2. In a process for the preparation ofa-acetamido-;8-hydroxypropiophenone, the step comprising reactinga-acetamidoacetophenone and formaldehyde while maintaining a pH in therange of from about 8.0 to about 9.0.

3. In a process for the preparation of anitroa-acetamido-fi-hydroxypropiophenone, the step comprising reactingan a-acetamidoaceto-nitrophenone and formaldehyde while maintaining a pHin the range of from about 8.0 to about 9.0.

4. A process as described in claim 3 wherein thenitro-a-acetamidoacetophcnone is p-nitroa-acetamidoacetophenone.

5. In a process for the preparation of anaacetamido-c-hydroxypropiophenone, the step comprising reacting a onemolecular proportion of an a-acetamidoacetophenone having the formulawherein R represents a phenyl radical selected from the class consistingof the unsubstituted phenyl radical and substituted phenyl radicalscontaining as their substituent groups halogens, nitro groups, alkylgroups, and alkoxy groups; and at least a one molecular proportion offormaldehyde while maintaining a pH in the range of from about 8.0 toabout 9.0.

6. In a process for the preparation ofe-acetamido-;8-hydroxypropiophenone, the step comprising reacting a onemolecular proportion of a.- acetamidoacetophenone and at least a onemolecular proportion of formaldehyde while maintaining a pH in the rangeof from about 8.0 to about 9.0.

7. In a process for the preparation of a nitroa-acetamido-{3-hydroxypropiophenone, the step comprising reacting a, onemolecular proportion 0 R-L-(FH: NH O=?-CH: wherein R. represents aphenyl radical selected from the class consisting of the unsubstitutedphenyl radical and substituted phenyl radicals containing as theirsubstituent groups halogens, nitro groups, alkyl groups, and alkoxygroups; and an aqueous solution containing at least a one molecularproportion of formaldehyde while maintaining a pH in the range of fromabout 8.0 to about 9.0.

10. In a process for the preparation of an a.- acetamido-8-hydroxypropiophenone, the step comprising reacting a one molecularproportion of an a-acetamidoacetophenone having the formula O R-A-CH:

H O=!l-OH: wherein R represents a phenyl radical selected from the classconsisting of the unsubstituted phenyl radical and substituted phenylradicals containing as their substituent groups halogens, nitro groups,alkyl groups, and alkoxy groups; and an aqueous solution containing atleast a one molecular proportion of formaldehyde while maintaining a pHin the range of from about 8.0 to about 9.0 and a temperature in therange of from about 20 C. to about C.

11. A process as described in claim 10 wherein them-acetamidoacetophenone is p-nitro-a-acetamidoacetophenone.

12. In a process for the preparation of anaacetamido-,3-hydroxypropiophenone, the step comprising reacting a onemolecular proportion of an a-acetamidoacetophenone having the formula 0RJI ICHz NH O=!7-OHs wherein R represents a phenyl radical selected fromthe class consisting of the unsubstituted phenyl radical and substitutedphenyl radicals containing as their substituent groups halogens, nitrogroups, alkyl groups, and alkoxy groups; and an aqueous solutioncontaining at least a one molecular proportion of formaldehyde at atemperature in the range of from about 20 C. to about 50 C. whilemaintaining a pH in the range of from about 8.0 to about 9.0 by theaddition of an alkali metal bicarbonate and acetic acid.

13. A process as described in claim 12 wherein thea-acetamidoacetophenone is p-nitro-a-acetamidoacetophenone.

OLIVER DE GARMO. DAVID B. GUTHRIE.

References Cited in the file of this patent UNITED STATES PATENTS

1. IN A PROCESS FOR THE PREPARATION OF ANAACETAMIDO-B-HYDROXYPROPIOPHENONE, THE STEP COMPRISING REACTING ANA-ACETAMIDOACETOPHENONE HAVING THE FORMULA